The present invention relates to compositions and methods for alleviating symptoms associated with perimenopausal and/or menopausal disorder or discomfort.
While Phosphatidyl-L-serine (PS) has been implicated in treatments for premenstrual syndrome (PMS) (alone and in conjunction with phosphatidic acid (PA)), as well as for cognitive disorders such as stress, very little has been shown regarding PA monotherapy treatments. PA was shown to be effective in treating PMS both alone and in conjunction with bio-available magnesium.
Recently, studies have substantiated that there is a synergistic mechanism by which PS and PA (the combination referred to herein as PAS) operate with regard to stress reactivity in men (see Hellhammer et al., Lipids in Health and Disease, 2014, 13, 121). Chronic stress has been shown to reduce cortisol binding globulin (CBG)—a glycoprotein synthesized in the liver, and secreted in the blood which binds with a high affinity, but low capacity, in the blood to glucocorticoid hormones, such as cortisol in humans and corticosterone in laboratory rodents. A drop of CBG in chronically-stressed subjects was hypothesized therein to explain that PAS first causes a normalization of CBG levels under such conditions, which then result in a normalization of the activity and reactivity of the HPAA (Hypothalamic-Pituitary-Adrenal Axis).
PS and PA, while both being phospholipids, have distinct physicochemical properties which lead to divergent physiological behavior. With regard to the distribution of PLs in the human body, it is widely known that PS is concentrated primarily in the brain as well as to some extent in the central nervous system (CNS), while PA in contrast is distributed throughout the body (see “The Distribution of Phosphatidyl-D-serine in the Rat” by Omori et al. Biosci. Biotechnol. Biochem., 2010, 74(9), 1953-1955; and “Phosphatidylserine: structure, occurrence, biochemistry and analysis” by Christie, AOCS Lipid Library, http://lipidlibrary.aocs.org/Lipids/ps/index.htm, 2013).
Via hydrolysis, many PLs serve as precursors to important biochemical agents in the body. For example, PC is known to release choline which acts as a precursor for production of acetylcholine, a known neurotransmitter. Similarly, PS releases L-serine in the brain which undergoes conversion to D-serine via an isomerase racemase (an isomerase enzyme which catalyzes the stereochemical inversion around the asymmetric carbon atom in biological molecules having only one center of asymmetry). D-serine has been implicated in many physiological and neurological therapeutic remedies.
Under physiological conditions, serine binds phosphate through its free hydroxyl (—OH) group to form the phosphate ester of PS. The head group of PS has three charged groups: a positively-charged primary amine, a partially negatively-charged carboxyl group, and a negatively-charged phosphate group. Thus, PS has a net negative charge in equilibrium due to its carboxylate group. In PA, two free hydroxyl groups are available for ionization. The first hydroxyl group is readily ionized in equilibrium at a pH greater than 2. The second hydroxyl group is predominantly ionized in equilibrium at a pH typical of physiological environments.
While PA is known to undergo cleavage of its beta-position fatty acid to form lysophosphatidic acid (LPA, an important implicated precursor), the double negative charge of the phosphate group of PA as explained above stands out in stark contrast to all other PLs, including PS, which have less negatively-charged phosphate moieties. Such physicochemical properties make PA impermeable in the brain (i.e., the so-called Blood-Brain Barrier (BBB) separating circulating blood from the brain extracellular fluid (BECF) in the CNS) (see article on “Phosphatidic Acid,” Wikipedia, http://en.wikipedia.org/wiki/Phosphatidic_acid).
A scientific publication by Montané and Pérez-Balllester (J. Reprod. Fert., 1985, 73, 317-321) on “Cyclic changes in phospholipid content and composition in human endometrium during the menstrual cycle” states, “A significant increase in total phospholipid content of the endometrium took place during the secretory phase of the human menstrual cycle (26% increase from mid-proliferative to premenstrual stage). The major phospholipid, phosphatidylcholine, was increased by 30%, whereas phosphatidylethanolamine was unchanged. Phosphatidyl-serine and -inositol underwent the largest percentage increases (40%). Phosphatidic acid levels were the only ones to decrease (−52%), a finding consistent with the role of this lipid as precursor of the increased phospholipids.”
The statements above indicate that human cyclic changes in phospholipid content during a women's PMS phase predominantly concern PS, PI, and PC (PE showed zero change). PC, PI, and PE are readily available in normal diets, and therefore are excluded from attribution of any therapeutic effects. However, PS and PA are not readily available in normal diets. The fact that the PA levels decreased dramatically during the menstrual-cycle study stands in sharp contrast to the increase observed in the PS levels. Thus, it would not be considered a reasonable assumption to extrapolate the effectivity of PS to PA in the treatment of PMS.
PMS has been shown (see Freeman et al., Obstetrics and Gynecology, May 2004, 103, 960-965) to have a direct correlation with menopause in the sense that women who suffer from PMS symptoms have a high likelihood of suffering later in life during the transition to menopause (known as perimenopause) as well.
With regard to magnesium, it is estimated that the binding of Mg (as Mg2+) to PA is at least ten times stronger than Mg to PS. Thus, in the presence of PS and PA, Mg would be expected to preferentially bind to PA; in isolation (i.e., given only PA and Mg), PA would be expected to scavenge and selectively bind any bio-available Mg.
It would be desirable to have compositions and methods for alleviating symptoms associated with perimenopausal and/or menopausal disorder and discomfort.